Pyridine derivatives

ABSTRACT

The disclosure relates to novel bis(pyridinium quaternary salts), a process for their manufacture, compositions containing them, and a method of preventing the growth of, or killing, bacteria by applying one of the novel pyridinium salts to a bacterially infected environment.

United States Patent 11 1 [111 3,875,174

Edwards Apr. 1, 1975 PYRIDINE DERIVATIVES [58] Field of Search. 260/294.8 R, 295 AM, 295 Q, [75] Inventor: Philip Neil Edwards, Macclesfield, 260/295 2948 295 295 296 D England Assi I W I Ch H d t [56] References Cited gnee: in ma emlca n us ries,

Limited, London, England UNITED STATES PATENTS 3,251,839 5/1966 Downes et al. 260/295 0 1 Flledl 27, 1973 3,586,686 6/1971 Braunholtz 260/2948 R [2|] Appl. No.2 428,677

Primary E.\'aminer--Alan L. Rotman Relmed pp Dam Attorney, Agent, or Firm-Cushrhan, Darby & [62] Division of Scr. No. 234.648, March 14, 1972, Pat. Cushman 3 F A r P t D [57] ABSTRACT I 1 :relgn pp lc atlon y The disclosure relates to novel bis(pyridinium quater- Mar -9, 197] United Kingdom 807l/7i nary salts), a process for their manufacture composi tions containing them, and a method of preventing the [52] 260/2943 260/268 260/240 growth of, or killing, bacteria by applying one of the 260/240 E, 260/240 1, 260/295 E, 260/295 AM, 260/295 Q. 260/2955 A, 260/2955 D, 260/295 S, 424/250, 424/263 lnt. Cl C07d 31/48 novel pyridinium salts to a bacterially infected environment.

5 Claims, N0 Drawings PYRIDINE DERIVATIVES This is a division. of application Serial No. 234,648 filed Mar. 14, 1972, now US. Pat. No. 3,786,058.

This invention relates to novel pyridine derivatives which possess valuable antibacterial properties and some of which are useful in dental hygiene for inhibiting the formation of dental plaque.

According to the invention there is provided a pyridine derivative of the formula:

/ A l 2 I A R A2R2 wherein R and R which may be the same or different, are each an alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl. alkanoyloxyalkyl or aryloxyalkyl radical of at least 6 and not more than 14 carbon atoms, a phenyl or naphthyl radical containing to 3 halogen atoms, or an alkyl radical of l to 3 carbon atoms which is substituted by a phenyl or naphthyl radical which is itself substituted by 0 to 3 halogen atoms or alkyl or alkoxy radicals of l to 6 carbon atoms; A and A which may be the same or different, are each a direct linkage or a linking group of the formula CH CO.NHwherein the methylene radical is joined to the pyridine nitrogen atom; (X. X'-)'- represents two monoanions or a dianion; and A" is a linking group selected from 3. (CH- ),,O(CH provided that both ns are not 0,

4. (CH ),,.N(COR)(CH wherein R is an alkyl or aryl radical of up to 10 carbon atoms, and provided that both as are not 0,

5. CH:CH.Y.CH:CH-

6. CO.NHNH.CO(CH2)".(CO),.NHNH.CO

7. CO.NHNH.CO.Y.CO.NHNH.CO

wherein n is 0, l or 2; m is 0 to 12;.r is 0 or 1; is 0 or 2 to 6; z is 2 or 3; Y is a phenylene or naphthylene radical; and Z is a straightor branched-chain alkylene radical of 2 to 8 carbon atoms.

When R and R are alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkanoyloxyalkyl or aryloxyalkyl radicals, they are preferably straight-chain such radicals, for example n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-undec-l0-enyl, 2-nhexyloxyethyl or 2(2-butoxyethoxy)ethyl radicals. When R and R are phenyl or naphthyl radicals containing O to 3 halogen atoms, or are alkyl radicals of l to 3 carbon atoms substituted by a phenyl or naphthyl radical which is itself substituted by 0 to 3 halogen atoms or alkyl or alkoxy radicals of l to 6 carbon atoms, such halogen atoms may be, for example, chlorine or bromine atoms, and the alkyl radical of l to 3 carbon atoms may be, for example, the methyl radical, so that R and R may be, for example, 3.4- dichlorophenyl, 4-chlorobenzyl, 2,4-dichlorobenzyl or 2-naphthylmethyl radicals.

When (X.X represents two monoanions, suitable anions are, for example, halide anions. for example chloride or bromide anions, anions derived from a carboxylic acid, for example the acetate anion, or anions derived from a sulphonic acid, for example the methanesulphonate or toluene-p-sulphonate anions; and when (X.X represents a dianion, a suitable anion is, for example, the sulphate or phosphate anion.

It is to be understood that although (X.X") represents two monoanions or a dianion, the corresponding monovalent radicals or atoms are X and X and the corresponding divalent radical is (X.X Thus, for example, X and X may each be chlorine or bromine atoms, or methanesulphonyl, toluenesulphonyl or acetoxy radicals, and (X.X") may be, for example, the sulphate divalent radical.

A suitable phenylene or naphthylene radical is, for example, the o-phenylene, m-phenylene, p-phenylene, l,4-naphthylene, 1,5-naphthylene, 4-methyl-1 ,2- phenylene, 2,5-dimethyl-1,4-phenylene, 2,5-dimethoxy-l,4-phenylene or 2,4,5,6-tetrachlorol,3-phenylene radical.

A suitable value for Z is, for example, the ethylene, trimethylene, hexamethylene or 2,2- diethyltrimethylene radical.

Preferred linking groups A are those numbered 1, 2, 6. 8.9. ll, I2, l4, 15, 17, 18.23.24, 25,26, 27,28 and 29 in the list above, and of these, particular linking groups A are:

Preferred compounds of the invention are those wherein the radicals -AR and -A R are the same, and a preferred group of pyridine derivatives of the invention comprises those compounds of the formula 1 above wherein A and A are each a direct linkage. R and R are each the same alkyl or alkenyl radical of 8 to l 1 carbon atoms. (X.X represents two bromide, chloride, methanesulphonate, toluene-p-sulphonate or acetate anions, or the sulphate dianion, and A is:

NH.CO.NH-

A particularly preferred sub-group within the above group comprises those compounds wherein A and A are each a direct linkage, R and R are each an unbranched alkyl radical of 8 to l 1 carbon atoms. optionally containing a terminal double bond, (X.X represents two bromide. chloride, methanesulphonate, toluene-p-sulphonate or acetate anions, or the sulphate dianion, and A is the trimcthylene or ureylene radical or a radical of the formula NH.CO(Cl-l -CO.NH, and especially those compounds wherein A is linked to the same numbered carbon atom of each pyridine ring.

Particular new pyridine derivatives of the invention are described in Examples l to 4, and of these, individual, specially preferred derivatives are 4,4- trimethylenebis( l-n-decylpyridinium methanesulphonate (compound 5 3,3'ureylenebis(1-ndecylpyridinium methanesulphonate), (compound 3,3'-ureylenebis( l-n-decylpyridinium chloride), (compound 26); 3,3'-glutaramidobis(l-n-decylpyridinium chloride). (compound 78); 3,3glutaramidobis( l-ndecylpyridinium methanesulphonate), (compound 79); 3,3'-adipamidobis(l-n-decylpyridinium methanesulphonate), (compound 4,4'-adipamidobis( l-ndecylpyridinium methanesulphonate), (compound 82); 3.3-pimelamidobis( ln-decylpyridinium chloride), (compound 86): 3,3 '-suberamidobis( l-ndecylpyridinium chloride), (compound 87); 3,3- suberamidobis(l-n-dccylpyridinium methanesulphonate (compound 88); 3.3 '-azelamidobis( l-ndecylpyridinium methanesulphonate), (compound 90): 3,3'selmcamidobistl-noctylpyridinium methanesulphonate), (compound 31): and 3,3'-sebacamidobis( ln-decylpyridinium methanesulphonate), (compound 32).

According to a further feature of the invention there is provided a process for the manufacture of the novel pyridine derivatives of the invention which comprises:

a. the quaternisation of a pyridine derivative of the formula:

with a quaternising agent or quaternising agents (RA).X, (R A ).X or (RA)(R A ).(X.X) wherein A, A A", R and R have the meanings stated above and X, X and (X.X) are radicals derived from the acids HX, HX and H (X.X) respectively, which are strong acids; or

b. the quaternisation of a pyridine derivative of the formula:

A III E with a quaternising agent (R A ).X, wherein A, A A R, R X and X have the meanings stated above;

c. for those compounds wherein the linking group A contains one or two amide linkages, the reaction of a mono-carboxylic acid of the formula:

l coon.

or a reactive derivative thereof, with a suitable monobasic or dibasic compound, or the reaction of an amine of the formula:

, l P (CH .NH (x J with a suitable monoor dicarboxylic acid, or a reactive derivative thereof wherein A, R, X and n have the meanings stated above; or

d. for those compounds wherein the linking group A contains one or two urea linkages, the reaction of an amine of the formula V with a monoor di-isocyanate, or the reaction of an isocyanate of the formula:

amino compound of the formula V with a suitable bischloroformate ester, or the reaction of a chloroformate ester of the formula:

. 1 (ca .o.c0c1. (x VII wherein A, R, X and n have the meanings stated above, with a suitable dibasic compound: or

g. for those compounds wherein the linking group A contains two urethane linkages, the reaction of a hydroxy compound of the formula:

with a suitable di-isocyanate, or the reaction of an isocyanate of the formula:

with a suitable dihydroxy compound wherein A, R, X and n have the meanings stated above; or

h. for those compounds wherein the linking group A contains one or two olefinic linkages, the reaction of an activated methylpyridinium salt of the formula:

,i (-1 CH3. (x

wherein A, R and X have the meanings stated above, with a suitable monoor di-aldehyde; whereafter if desired a product thus obtained containing an anion (X (X) or (X.X") is converted to a corresponding compound containing a different anion (X), (X or (X.X by basification thereof followed by reaction of the basified product with an acid HX, HX or H (X.X-) wherein X, X X and X have the meanings stated above, or by an ion-exchange resin.

The quaternisation process is preferably carried out by heating together the pyridine derivative and quaternising agent, and the inclusion ofa solvent, for example nitrobenzene. sulpholane or toluene, is often advanta geous in improving the mutual solubilities of the reactants, or to moderate the reaction. The addition of a tertiary amine, for example a hindered tertiary amine such as di-isopropylethylamine is also useful, for removing any acid generated during the reaction.

The processes 0) to h) for the formation of amide, urea, urethane or olefin linkages may be carried out in generally known manner described in the literature for analogous compounds.

A suitable strong acid HX HX or H:(X.X*) has a pk,, value of less than 2, and is, for example, hydrochloric, hydrobromic, methanesulphonic, toluene-psulphonic or sulphuric acid.

As stated above. the new compounds of the invention possess valuable antibacterial properties. in that they are effective against a wide range of both Grampositive and Gram-negative organisms, including strains of, for example, Pseudomonads which are resistant to other widely-used antibacterial agents. Further advantages of the preferred compounds of the invention may include, for example, rapid speed of kill. being bactericidal rather than bacteristatic, not being deactivated by hard water. or having more surface activity. Further, textile materials which have been in contact with the compounds of the invention are not stained by treatment with hypochlorite bleach.

Thus. according to a further feature of the invention. there is provided a composition comprising at least one pyridine derivative of the invention together with an inert diluent or carrier.

The composition of the invention may be a pharmaceutical composition, for example in the form of a 102- enge suitable for oral administration. or an ointment, cream. or sterile aqueous or oily solution or suspension for topical use; or it may be a non-pharmaceutical composition, in the form of, for example, a non-sterilised aqueous or oily solution or suspension, or an aerosol, for use as a general. environmental antiseptic or disinfectant, or a mouthwash. paste, gel or fluid suspension suitable for use in dental hygiene for the inhibition of dental plaque formation.

The composition may contain conventional excipients and carriers, and may be manufactured by the application of conventional techniques.

Preferred pharmaceutical compositions of the invention are lozenges. each containing from 0.1 to 1.0% w/w ofa new compound ofthe invention, and preferred non-pharmaceutical compositions are an aqueous solution suitable for use as an antiseptic and containing from 0.02 to 1.0% w/v of a compound of the invention, an aqueous solution in the form of a concentrate containing from 1% w/w to that percentage which gives a saturated solution of a compound of the invention, or powder or tablets for dissolution in water to give an aqueous solution suitable for use as an antiseptic. Preferred compositions foruse in dental hygiene are mouthwashes containing between 0.05% and 0.5% w/v (at user dilution) of a compound of the invention; and toothpastes and dental gels containing between 0.05% and 1.0% w/w, preferably between 0.1% and 0.5% w/w, of a compound of the invention.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1 General procedure for quaternisation The pyridine derivative (0.01 mole) and the alkylating agent (0.02-0.1 mole) are heated together. optionally with inclusion ofa solvent, e.g. nitrobenzene to improve the mutual solubilities, or to moderate the reaction, and/or a hindered amine. for example diisopropylethylamine to remove any acid generated dur- 9 10 mg the reaction. The temperature and time of heating f are shown for each compound in the Tables, but these i 3 l 2 2 are not necessarily optimal conditions and they can A l (X usually be varied over wide ranges. The product 18 crysv tallised from a suitable solvent and, if required. the T r T anion can he changed by c0nvent|0nal procedures, for example h the use of ion-exchange resins.

N0 A I 2 1 2 First m! Second X linkuge Iinkage" l n-oetyl 4 -C H CH. 4 Ms" 2 n-decyl 4 CH CH 4 Ms 3 n-dodecyl 4 4 M5 4 n-octyl 4 4 Ms 5 n-deeyl 4 4 M 6 n-dodecyl 4 4 Ms 7 n-tetra- 4 4 Br decyl X n-decyl 4 4 M 9 n-undecyl 4 4 Br 10 n-dodeeyl 4 4 M ll CH CO 3.4-di- 4 4 c1 NH- chlorophenyl l2 n-oetyl 2 C H :CH- 2 Ms l3 n-deeyl 2 CH:CH 2 Ms l4 n-octyl 3 CH:CH- 3 I Ms l5 n-decyl 3 --CH:CH 3 Ms l6 n-dodecyl 3 CH:CH 3 Ms l7 n-octyl 3 CH:CH 4 Ms l8 n-deeyl 3 -CH:CH 4 Ms l9 Z-n-hexyl- 3 CH:CH 4 Ms oxyethyl 4-chloro- 3 CH:CH 4 Cl henzyl ll 2,4-di- 3 CH:CH 4 Cl chlorohenzyl 22 Z-nuphthyl- 3 CH:CH 4 Br methyl 3 23 n-deeyl 2 CH:CH- 3 Ms 24 n-octyl 3 -NH.CO.NH 3 Ms 25 n-dccyl 3 NH.CO.NH- 3 Ms 26 n-deeyl 3 NH.CO.NH 3 Cl 27 n-decyl 3 NH.CO.C OtNH 3 Ms 28 n-dccyl 3 NH.CO(CH 3 Ms CO.NH- 29 n-octyl 3 NH.C O( C H 3 Ms CQ.NH 30 ndecyl 3 NH.C0(CH- 3 Ms COLNH- 3] n-oetyl 3 NH-CO(C 2)x 3 Ms COLNH- 32 n-decyl 3 l lH.CO(CH- 3 Ms COINH- 33 n-decyl 3 3 Br 34 n-decyl 3 C .NH.CO(CH 3 Ms l CO.NH.CH 35 n-decyl 3 CH- ..NH.C0(CH 3 Ms CO.NH.CH 36 n-octyl 3 NH.CO 3 Ms 37 n-deeyl 3 "NH.(O- 3 Ms 38 n-octyl 3 NH.CO 4 Ms 3) n-decyl 3 NH.CO 4 Ms 40 n-octyl 3 CH- ,.NH.CO 3 Ms 4] n-decyl 3 -CH- ,.NH.CO 3 Ms 42 n-octyl 2 -CH .NH.CO 3 Ms 43 n-decyl 2 -CH- .NH.CO 3 Ms 44 n-octyl 3 C H .NH.CO 4 Ms 45 n-decyl 3 C H .NH.Co- 4 Ms 46 n-oetyl 2 CH .NH.CO 4 Ms 47 n-decyl 2 CH .NH.Co 4 Ms 48 n-octyl 4 CO.NH(CH:)-1 4 Ms NH.CO 49 n-decyl 4 CO.NH(CH 4 Ms NH.CO 50 n-decyl 4 CO.NH(CH- 4 Ms NH.CO

"linkage of left hand pyridine ring to A" in the formula us written at the head of the table.

""where A is not symmetrical. it should he read as from left to right in the formula at the heard of the table. ""linluige of A to right hand pyridine ring in the formula as written at the head of the tablet ""Ms=methanesulphontttev ""the methylene group is attached to the pyridine nitrogen atom. and the NH group is attached to R.

R111i911 wfldilivns tained b the followin rocess whi h e em NO Temp Time Additive M.P.(C.) f h g p X phfles the (minutes) preparation 0 t e un-quatermsed pyridine starting materm] for compounds 40 and 4]: I Nicotinoyl chloride (I4.lg. was added over ten 3 155 365467 5 minutes, with stirring and coolmg in an we bath, to a 4 170 m ldewmposition) solution of 3-amino-methylpyridine 10.8g.) and trieth- 5 in m 78:8] ylamine (l0.lg.)' in methylene chloride (50ml). After 6 120 87-89 the addition was complete, the mixture was stirred at Z 338 room temperature for an hour, diluted with water 9 130 10 315-317 10 (l00ml.). and the product was isolated from the or- II I 9g? ganic phase by evaporation of the solvent. The crude (dcwnqbgsmon, product was recrystallised from ethyl acetate, mp. 12 140 60 210-211 104 ]()6C 13 135 60 189-192 I4 125 30 73476 The followmg starting materials were prepared s1m1- 15 125 196-198 15 larly, using the appropriate acid chlorides and amino I6 135 30 204-208 com Ounds. 17 130 7 97-99 P 18 130 10 109-112 19 130 10 120" 20 95 5 248-250 5111111112 21 130 s 224-229 1319199111 22 130 4 273-276 20 -P- 23 130 60 2213-231 C911111Ounds 24 140 5 193-1985 25 l3() 5 233-234 26 195 10 DlE"" 23 244 27 290-292 27 I80 5 nitro- 239-243 28 236-238 benzene 29. 232-235 23 170 5 202-2045 25 32 161-164 29 160 5 186-190 34 196-2005 30 150 5 203-2065 184-1855 31 160 5 101-103 K 39 163-166 32 160 5 109.5-1 10.5 41 104-106 33 l40 20 nitro- Not crystalline 43 7578 benzene 44. 78-80 34 150 1 98-100 30 4947 83-85 35 I 15 l3l-l34 36 I30 l5 DIE 157-160 37 140 30 DIE l68-l7l 38 30 DE l50-l52 39 130 30 DIE 166-168 The unquaternrsed pyridme startmg material for 40 140 30 DIE 68-69 compound 32 is also a novel compound and may be 41 140 30 DIE 167-169 35 42 130 30 DlE l58-l60 prepared as follows: 43 130 DIE 3-Aminomethylpyridine (10.8g.) and diphenyl car- 44 130 30 DIE 167-170 o 45 130 60 DIE 634,4 bonate l0.7g.) were mlxed, heated together at C. is g}? -3 1 for five minutes. and the mixture was cooled and stirred 89- 48 30 DE l67468 40 mm ether. The product was filtered off, washed with 49 30 DlE 174-176 fresh ether, and recrystallised from ethyl acetate, mp. 50 I60 60 DIE 59-6] "approximalc m.p., compound very hygroscopic. ""DIE= di-isopropylelhyluminc. 2

Certain of the un-quaternised pyridines, wherein A 45 The process described in Example I is repeated. is an amide containing linkage. used as starting materiusing the appropriate bis-pyridine derivatives and quatals for the above compounds are novel, and may be obernising agents, to give the following compounds:

I A3 I x x 1 \q @T I A R A R l No. A. =A 1rst (b) 1 Second( l 21 linkage A llinkage C 1 1 2 i 1 51 CH co.- n-octyl 1 -c11 .cn I 11 c1 1 (c1) 2 2 1 NH- 5 I 1 i 52 -c11 co.- n-decyl 1 -c11 .c11 f 1 01 I l I I 1 $5) I 53 n-nonyl l CH:CH 1 i M I I 5 1 3,5,5- 1 -cH=cH- 1 1 Ms I I trime'chyll i 1 hexyl 1 l 1 1 Continued 1 2 1 2 First (b) Secon 1 2 No. A -A R -R linkagem) 5 i c) 81 2-heatyloxy- 3 -NH.CO(CH CO.NH 3 Ms ethyl 82 n-de'cyl -l -NH.CO(CH' CO.NH l MS 83 CH CO.- n-octyl 3 -NH.CO(CH: CO.NH- 3 Cl 8 4 undec- 3 NH.CO(CH' CO.NH- 3 Ms lO-enyl 85 -CH CO.- n-decyl 3 NH.CO(CH; CO.NH- 3 C1 86 n-decyl 3 NH.CO(CH; )5CO-NH- 3 C1 87 n-decyl 3 *NH.CO(CH' CO.NH 3 Cl 88 n-decyl 3 -NH.CO(CH; CO.NH 3 Ms 89 n-decyl NH.CO(CH' CO.NH- Ms 90 n-decyl 3 -NH.CO(CH2) CO.NH 3 Ms 91 n-decyl 2 -NH.CO(CHl CO.NH- 2 MS 92 2-(2- 3 NH.CO(CH' CO.NH- 3 MS butoxyethoxy)- ethyl 9?) n-decyl l -CH NH.C0(CH- CO.- 4 Ms NH H 2 9 4 n-decyl 3 NH.COO(CH OCO.N|H 3 Ms 95 n-decyl 3 NH.COO(CH' OCO.NlH- 3 MS 96 n-decyl 3 -NH.COO(CH OCO.N'H- 3 MS l 97 n-decyl 3 NH.COOCH C(C H CH 3 MS 5 OCO.NH 2 2 5% 2 98 n-decyl 3 -NH.CO [0(CH OCO.- 3 MS 2 2 2 I l 99 3,5,5- 3 Ll MS trimethylhexyl a. linkage of left hand pyridine ring to A in the formula l! f w o as written at the head of the table. 3 112 Adam b. where A is not symmetrical it should be read as from left to right in the formula at the head of the ta- 60 53 l0 25s c. linkage of A to the right hand pyridine ring in the a? formula as written at the head of the table. 5;, i I 5: d. the methylene group is attached .to the pyridine ni- 57 120 20 238- 2395 trogen atom and the NH group is attached to R. e. Ms=methanesulphonate. 5

-Continued Reaction conditions B. Certain other of the unquaternised pyridines, wherein A is a ureido-containing linkage, used as start- No. Temp. 'l'ime Additive M.P.(C.1 ing materials for the preparation of the above compounds of the invention, are novel and may be obtained 01 150 15 122425 as follows: (1: 100 112-11-1.5 (3 W) 2mm A solution of hexamethylene dl-lsocyanate (l.68g.) 0-1 195 10 2105-2125 in toluene (10ml) was added to a solution of 3- I f??? aminopyridine (1.88g.) in toluene 18ml.) and the mixin 193404 0 ture was heated on a steam-bath for 10 minutes. The 2 glj s l mixture was cooled. and the product was filtered off, 711 140 Is innit; washed with toluene and dried. to give l,6-bis[3- Z], 2- (pyrid-3-yl)ureido]hexane. m.p. l97l99C., the m5 55 535 starting material for compound 67. Q 32%? 15 In a similar manner. using 3-aminomethylpyridine in m) I i 13 place of 3-aminopyridine, there was obtained the start- 77 "j" ing material for compound 68, l,6-bis[3-(pyrid-3- 78 I50 (10 sulpholane 'll4.52l6.5 o o 79 14) 10 154455 ylmethyl)ure1dolhexane. nip. ..3 5 C. 80 2 2 2 C. Certain other of the unquarternised pyridines, 2; 5 B815: wherein A is a ureidoor urethane-containing linkage, 83 100 2 2-3 S used as starting materials for the preparation of the g 5" above compounds of the invention. are novel and may 1th 165 120 sulpholane 116-120 be obtained as follows:

+DlE" v 87 50 60 sulphnlune 3134M"; 2s A solution of tetramethylene d ianune (0.535g.) 1n xx 140 5 93.5-94.5 toluene 10ml.) was added with stirring and coolmg to $3 I 36 a solution of 3-pyridyl isocyanate (l.46g.) in toluene 91 190 15 l34-136 (l5ml.).The mixture was stirred until the reaction was 3% lg Z3 complete. and the product was filtered off. washed with 9'4 lid) 10 163-166 toluene and crystallised from ethanol to give 1,4-bisl3- 23 1 2 (pyrid-3-yl)ureido]hexane. m.p. 2182l9C., the 1, 55 m 3 starting material for compound 66. l5 ln asi ilar manner usin thea ro riateisoc anate 99 140 30 DIE 90-93 1 h .mmEzdimpnwmlmminc and the approprlate amine, iamme or 10 .t e o owing starting materials were prepared: A. Certain of the unquaternised pyridines, wherein 5mm, material A is an amide-containing linkage. used as starting mafor compounds nos. M.P. (C.) terials for the above compounds are novel. and may be 5 s 99 s obtained from the reaction of an appropriate amine zoj and an appropriate acid chloride by the process de- 40 76 1834845 scribed in the latter part of Example 1. 9 -1 2 95 189-190 96' 167-169 97 183-185 98 142-144 Starting material for compounds nos. M.p. (C.)

275-378 EXAMPLE 3 The process described in Example 1 is repeated usmg ,3 in; the appropriate bis-pyridine derivates and quaternising o4 304.5-308 50 agents, to give the following compounds: 189-191 77 I'll-224.5 78/79 190-1925 82 280-2111 3 86 206-2085 A l l 2 2 87/88 171.5-1735 s -X' 149 1995-2015 90 158460 5 9| 133.5- 93 139-141 q A R A 12 No. "A=A2 R'= 2 First A" Second X= linkage linkage" I00 n-dccyl 3 Nll.COCH CHCO.N- 3 Ms"" n1 l0l n-octyl 3 NH.CO(CH2OCH2)- 3 Br CO.NH I02 n-decyl 3 NH.COCH- OCH- -C- 3 Br ob11 co.1\11-1 I03 n-dccyl 3 NH.CO|O(CH- 3 Ms OCONH- 10-! n-dccyl 3 .(l\)'H.COO(CH- -)-;NH- 3 Ms ""linkage ol left hand pyridine ring to A in the formula as written at the head olthe table. ""where A is not symmetrical. it should he read as from left to right in the formula at the head olthc table. "linkage of A to the right hand pyridine ring in the formula as written at the head of the table.

""l indicates a trans double bond, ""Ms mcthancsulphonate,

The unquaternised pyridine derivatives used as starting materials in the preparation of compounds 100 and 101 are novel, may be prepared by the process described in the latter part of Examle l, and have melting points of 32l.5322.5C. and ll7l 19C. respectively.

The unquarternised pyridine derivatives used as starting materials in the preparation of compounds 103 and 104 are novel, may be prepared by the process described at (C) in Example 2, and have melting points of l2l-l23C. and l94l94.5C. respectively.

The unquaternised pyridine derivative used as starting material in the preparation of compound 109 may be obtained as follows: 7

Sodium hydride (1.32g.) was added portionwise under an atmosphere of nitrogen during 30 minutes, to a stirred solution of 3-hydroxypyridine (2.85g.) in dry dimethylsulphoxide (28ml.) cooled to below 25C. When reaction ceased, 1,6-di-bromohexane (3.66g.) was added dropwise with stirring and cooling, and the resulting mixture was stirred a further 3 hours. The mixture was poured into ice-water, and the percipitated product was filtered off and crystallised from petroleum ether (b.p. 6()-80C.), to give l,6-bis-pyrid-3- yloxyhexane, m.p. 85C.

In a similar manner, using the appropriate dibromides, there were obtained the butane (m.p. 95C.) and decane (m.p. 64C.) analogues, the starting materials for compounds 108 and 110 respectively.

EXAMPLE 4 The methanesulphonate salt, compound 32 (3g) was dissolved in water and excess 2N sodium hydroxide was added. A yellow viscous oil separated which was extracted into chloroform, The chloroform layer was washed with water. and then shaken with excess aqueous toluene-p-sulphonic acid. Ether was added to precipitate the toluene-p-sulphonate salt, which was crystallised from a mixture of acetone and acetonitrile, m.p. l27l29C.

The sulphate was prepared in similar manner, m.p. l46l47C.

The acetate (m.p. 8789C.) was prepared in similar manner, except that the new salt remained in the aqueous phase and was recovered by evaporation of the solvent and crystallisation of the residue from acetone.

EXAMPLE 5 Compositions containing a pyridine derivative of the invention may be prepared from any pyridine derivative of the invention described in the foregoing Examples by conventional procedures as illustrated below, where. it is to be understood, the particular pyridine derivative named may be replaced by an equipotent amount of any other pyridine derivative of the invention.

Lozenge A mixture of sucrose (92.5g.), magnesium stearate (lg.), gum acacia (3g), water (3ml.) and 3,3- suberamidobis( l-n-decylpyidinium chloride) (0.5g.) is blended and compressed into hard lozenges such that each weighs lg., and contains 5mg. of the antibacterial pyridine derivative.

Antiseptic 3,3-Suberamidobis(l-n-decylpyridinium methanesulphonate) (0.5g.) is dissolved in eterile distilled water (99.5ml.) to give a liquid composition suitable for use as an antiseptic.

Toothpaste A solution is prepared by stirring saccharin sodium (0.2g.) in purified water (38.8ml.) to which is then added isopropanol (4.0g.) and glycerin (20g) (Solution I).

A mixture of oil of peppermint (0.6g) and oil of spearmint (0.3g) is added to Pluronic P"(O.6g. pluronic' is a trade mark) followed "by 4,4- glutaramidobis( l-n-decyl-pyridinium methanesulphonate) (0.5g.) and stirring is continued until a homogeneous solution is formed (Solution ll).

Solution l is slowly added to Solution II, with stirring, and natrosol 250HH (lg. Natrosol is a trade mark) is then added, stirring being continued until hydration is complete. A mixture of dic'alcium phosphate (20g), Neosyl E. T. (10g), titanium dioxide (lg.) and dried aluminium hydroxide gel (lg) is then added and mixing is continued until a smooth and uniform paste is formed.

What we claim is:

1. A pyridine derivative of the formula:

wherein R and R which may be the same or different are each alkyl having 8 to 14 carbon atoms, n-undcclO-yl. Z-n-hexyloxyethyl. 2-(2butoxyethoxy-ethyl). 3,4-dichlorophenyl. 4-chlorobenzyl. 2,4- dichlorobenzyl or Z-naphthylmethyl; A and A are each a direct linkage or a linking group of the formula CH ,CO.NH wherein the methylene is joined to the pyridine nitrogen; (X.X represents two monoanions or a dianion selected from the group consisting of two halide, methanesulphonate, toluene-p-sulphonate or acetate ions or the sulphate dianion;-and A is a linking group of the formula:

wherein m is O to 12.

2. The pyridine derivative of claim 1 wherein R and R are the same and are each n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl. n-tetradecyl, n-undeclO-enyl, 2-n-hexyloxyethyl, 2-(2-butoxyethoxy)ethyl, 3,4- dichlorophenyl. 4-chlorobenzyl, 2,4-dichlorobenzyl or Z-naphthylmethyl.

4. A pyridine derivative as claimed in claim 1, said derivative being 4,4'-( l,6-hexylenediamino)bis( l-n decyl-pyridinium bromide).

5. A pyridine derivative as claimed in claim 1, said derivative being 2,2-(LIO-decyIenediamino) bis( l-ndecyl-pyridinium methanesulphonate l l =l 

1. A PYRIDINE DERIVATIVE OF THE FORMULA:
 2. The pyridine derivative of claim 1 wherein R1 and R2 are the same and are each n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-undec-10-enyl, 2-n-hexyloxyethyl, 2-(2-butoxyethoxy)ethyl, 3,4-dichlorophenyl, 4-chlorobenzyl, 2,4-dichlorobenzyl or 2-naphthylmethyl.
 3. The pyridine derivative of claim 1 wherein A1 and A2 are each a direct linkage, R1 and R2 are each the same unbranched alkyl of 8 to 11 carbon atoms, (X1.X2)2 represents two bromide, chloride, methanesulphonate, toluene-p-sulphonate or acetate anions or The sulphate dianion, and A3 is a linking group of the formula: -NH(CH2)2-10NH-.
 4. A pyridine derivative as claimed in claim 1, said derivative being 4,4''-(1,6-hexylenediamino)bis(1-n-decyl-pyridinium bromide).
 5. A pyridine derivative as claimed in claim 1, said derivative being 2,2''-(1,10-decylenediamino) bis(1-n-decyl-pyridinium methanesulphonate). 